Many drugs, proteins and peptides for use in medical therapy are susceptible to degradation at the site of administration. In addition, many of these therapeutic agents have very short in vivo half-lives. Consequently, multiple injections or multiple oral doses are required to achieve desirable therapy. It is desirable to increase the therapeutic efficacy of these therapeutic agents containing active ingredients by using parenterally administrable sustained release formulations with controlled release of the therapeutic agents.
A formulation intended for parenteral use has to meet a number of requirements in order to be approved by the regulatory authorities for use in humans. It has to be biocompatible and biodegradable and all substances used and their degradation products should be non-toxic. In addition, particulate therapeutic agents intended for injection have to be small enough to pass through the injection needle, which preferably means that they should be smaller than 200 microns. The agent should not be degraded to any large extent in the formulation during production or storage thereof or after administration and should be released in a biologically active form with reproducible kinetics.
Various dosage forms have been proposed for therapeutic agents that require parenteral administration. For example, an agent may be microencapsulation by a phase separation process using a coacervation agent such as mineral oil, vegetable oils or the like, resulting in the formation of a microparticle containing the agent.
Another microencapsulation method entails formation of a three-phase emulsion containing a therapeutic agent, a polymer, and water. A drying step yields microparticles of the agent microencapsulated in the polymer.
Also reported is the formation of microparticles by spray drying, rotary disc, or fluidized bed techniques combining biodegradable polymers and therapeutic agents.
As mentioned above, there is a need to control the release of the microencapsulated therapeutic agent from a parenterally administrable sustained release formulation of microparticles in an accurate way. Often, the initial release rate of agent is large. This is known as the initial burst of the agent from the microparticle. In many of the controlled release systems based on biodegradable polymers, the release rate and initial burst of the therapeutic agent is largely dependent on the amount of agent incorporated into the microparticle. This is due to the formation of channels in the microparticles at higher agent loadings.
A well-known way of controlling the release of therapeutic agent from solid core is to apply a synthetic, biodegradable polymer coating that produces a rate controlling film on the surface of the core particles. The release rate and initial burst of the therapeutic agent is controlled by factors including the thickness of the coating, the diffusivity of agent through the synthetic polymer comprising the coating, and the rate of biodegradation of the polymer.
Often, the method of applying the coating requires use of solvents to dissolve the coating polymer prior to the coating process. This is done in cases where the melting temperature of the polymer is high enough to cause changes in the performance of the agent.
Synthetic polymers may include aliphatic polyesters, polyanhydrides and poly(orthoester)s. Synthetic absorbable polymers typically degrade by a hydrolytic mechanism. Such synthetic absorbable polymers include homopolymers, such as poly(glycolide), poly(lactide), poly(e-caprolactone), poly(trimethylene carbonate) and poly(p-dioxanone), and copolymers, such as poly(lactide-co-glycolide), poly(e-caprolactone-co-glycolide), and poly(glycolide-co-trimethylene carbonate). The polymers may be statistically random copolymers, segmented copolymers, block copolymers or graft copolymers.
Alkyd-type polyesters prepared by the polycondensation of a polyol, polyacid and fatty acid are used in the coating industry in a variety of products, including chemical resins, enamels, varnishes and paints. These polyesters also are used in the food industry to make texturized oils and emulsions for use as fat substitutes.
There is a great need for polymers for use as coatings in parenteral therapeutic agent delivery, where the polymers have both low melting temperatures and low viscosities upon melting, thus permitting for solvent-free processing techniques in preparation of parenteral therapeutic agent delivery compositions, can crystallize rapidly, and biodegrade within 6 months.